Dose-dependent effects of the Cimicifuga racemosa extract Ze 450 (drug simidona) in the treatment of climacteric complaints a randomized placebo-controlled study

Ruediger Schellenberg, Reinhard Saller, Lorenzo Hess, Jorg Melzer, Christian Zimmermann, Juergen Drewe, Catherine Zahner

Abstract


Since large epidemiological studies with long-term hormonal replacement therapy have shown a small but significantly increased risk for the development of invasive breast cancer, there is an increasing interest in nonhormonal treatment modalities for patients with climacteric symptoms.

Cimicifuga racemosa is a perennial medicinal plant native to North America where it has been used for centuries in indigenous medicine for the treatment of various conditions. Extracts from Cimicifuga racemosa (CR, synonym Actaea racemosa) have shown efficacy in trials in women with menopausal symptoms. Yet, dose dependency remains unclear. Therefore, 180 female outpatients with climacteric complaints were treated for 12 weeks in a randomized, double-blind, placebo-controlled, 3-armed trial (CR extract Ze 450 in 6.5 mg or 13.0 mg, or placebo). The study took place in four outpatient clinics.

Primary outcome was the difference in menopausal symptoms (vasomotor, psychological, and somatic), assessed by the Kupperman Menopausal Index between baseline and week 12.

Secondary efficacy variables were patients’ self-assessments of general quality of life, responder rates, and safety.

Compared to placebo, patients receiving Ze 450 showed a significant reduction in the severity of menopausal symptoms in a dose-dependent manner from baseline to endpoint (mean absolute differences 17.0 (95% CI 14.65–19.35) score points, р < 0.0001 for 13.0 mg; mean absolute differences 8.47 (95% CI 5.55–11.39) score points, р = 0.0003 for 6.5 mg). Quality of life and responder rates corresponded with the main endpoint. Changes in menopausal symptoms and quality of life were inversely correlated. Reported adverse events and clinical laboratory testing did not raise safety concerns. The CR extract Ze 450 is an effective and well-tolerated nonhormonal alternative to hormone treatment for symptom relief in menopausal women.


Keywords


Cimicifuga racemosa; menopause; vasomotor symptoms; non-hormonal therapy; randomized study

References


Dennerstein, L., Guthrie, J., Birkhäuser, M., et al. “Symptoms of the menopause.” In International Position Paper on Women’s Health and Menopause: A Comprehensive Approach, ed. by N.K. Wenger, C.J.M. Lenfant, R. Paoletti, and V.W. Pinn. NIH Publication 02–3284. National Heart, Lung, and Blood Institute. Office of Research in Woman’s Health (2002).

Green, R., Santoro, N. “Menopausal symptoms and ethnicity: the Study of Women’s Health Across the Nation.” Women’s Health 5.2 (2009): 127–33.

Thurston, R.C., Joffe, H. “Vasomotor symptoms and menopause: findings from the study of women’s health across the nation.” Obstet Gynecol Clinics of North America 38.3 (2011): 489–501.

Kronenberg, F. “Hot flashes: epidemiology and physiology.” Annals of the New York Academy of Sciences 592 (1990): 52–86.

Nakano, K., Pinnow, E., Flaws, J.A., et al. “Reproductive history and hot flashes in perimenopausal women.” Journal of Women’s Health 21.4 (2012): 433–9.

Hunter, M.S., Gentry-Maharaj, A., Ryan, A., et al. “Prevalence, frequency and problem rating of hot flushes persist in older postmenopausal women: Impact of age, body mass index, hysterectomy, hormone therapy use, lifestyle and mood in a cross-sectional cohort study of 10 418 British women aged 54–65.” An International Journal of Obstetrics and Gynaecology 119.1 (2012): 40–50.

Joffe, H., Soares, C.N., Cohen, L.S. “Assessment and treatment of hot flushes and menopausal mood disturbance.” Psychiatric Clinics of North America 26.3 (2003): 563–80.

Ohayon, M.M. “Severe hot flashes are associated with chronic insomnia.” Archives of Internal Medicine 166.12 (2006): 1262–8.

MacLennan, A., Lester, S., Moore, V. “Oral oestrogen replacement therapy versus placebo for hot flushes.” Cochrane Database Sys Rev 1 (2001): CD002978.

Maclennan, A.H., Broadbent, J.L., Lester, S., Moore, V. “Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes.” Cochrane Database Sys Rev 4 (2004): CD002978.

Sturdee, D.W. “The menopausal hot flush – anything new?” Maturitas 60.1 (2008): 42–9.

Collaborative Group on Hormonal Factors in Breast Cancer. “Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52.705 women with breast cancer and 108.411 women without breast cancer.” Lancet 350.9084 (1997): 1047–59.

Beral, V. “Breast cancer and hormone-replacement therapy in the Million Women Study.” Lancet 362.9382 (2003): 419–27.

Chlebowski, R.T., Hendrix, S.L., Langer, R.D., et al. “Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the women’s health initiative randomized trial.” Journal of the American Medical Association 289.24 (2003): 3243–53.

Stefanick, M.L., Anderson, G.L., Margolis, K.L., et al. “Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy.” Journal of the American Medical Association 295.14 (2006): 1647–57.

ESCOP, Cimicifugae Rhizoma. Black Cohosh, ESCOP Monographs, Scientific Foundation for Herbal Medicinal Products. Georg Thieme-Verlag. Stuttgart. Germany. 2nd edition (2003).

Committee on Herbal Medicinal Products (HMPC). “Community herbal monograph on Cimicifuga racemosa (L.) Nutt., rhizoma., European Medicines Agency.” Vol. EMA/ HMPC/600717/2007 (2010).

Reed, S.D., Newton, K.M., LaCroix, A.Z., et al. “Vaginal, endometrial, and reproductive hormone findings: Randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) Study.” Menopause 15.1 (2008): 51–8.

Wuttke, W., Gorkow, C., Seidlova-Wuttke, D. “Effects of black cohosh (Cimicifuga racemosa) on bone turnover, vaginal mucosa, and various blood parameters in postmenopausal women: a double-blind, placebo-controlled, and conjugated estrogens-controlled study.” Menopause 13.2 (2006): 185–96.

Wuttke, W., Seidlova-Wuttke, D., Gorkow, C. “The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers.” Maturitas 44 (2003): 67–77.

Oktem, M., Eroglu, D., Karahan, H.B., et al. “Black cohosh and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized trial.” Advances in Therapy 24.2 (2007): 448–61.

Ruhlen, R.L., Sun, G.Y., Sauter, E.R. “Black cohosh: insights into its mechanism(s) of action.” Integrative Medicine Insights 3 (2008): 21–32.

Osmers, R., Friede, M., Liske, E., et al. “Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms.” Obstet Gynecol 105.5.1 (2005): 1074–83.

Stoll, W. “Phytotherapeuticon influences atrophic vaginal epithelium.” Therapeutikon 1.23 (1987): 23–31.

Liske, E., Hänggi, W., Henneicke-von Zepelin, H.-H., et al. “Physiological investigation of a unique extract of black cohosh (Cimicifugae racemosae rhizoma): A 6-month clinical study demonstrates no systemic estrogenic effect.” Journal of Women’s Health and Gender-Based Medicine 11.2 (2002): 163–74.

Bai, W., Henneicke-von Zepelin, H.-H., Wang, S., et al. “Efficacy and tolerability of a medicinal product containing an isopropanolic black cohosh extract in Chinese women with menopausal symptoms: a randomized, double blind, parallelcontrolled study versus tibolone.” Maturitas 58.1 (2007): 31–41.

Aidelsburger, P., Schauer, S., Grabein, K., et al. “Alternative methods for the treatment of post-menopausal troubles.” GMS Health Technology Assessment 8 (2012): Doc03.

Borrelli, F., Ernst, E. “Alternative and complementary therapies for the menopause.” Maturitas 66.4 (2010): 333–43.

Wong, V.C.K., Lim, C.E.D., Luo, X., Wong, W.S.F. “Current alternative and complementary therapies used in menopause.” Gynecological Endocrinology 25.3 (2009): 166–74.

Palacio, C., Masri, G., Mooradian, A.D. “Black cohosh for the management of menopausal symptoms: a systematic review of clinical trials.” Drugs and Aging 26.1 (2009): 23–36.

Shams, T., Setia, M.S., Hemmings, R., et al. “Efficacy of black cohosh-containing preparations on menopausal symptoms: a meta-analysis.” Alternative Therapies in Health and Medicine 16.1 (2010): 36–44.

Kupperman, S., Wetchler, B.B., Blatt, M.H. “Contemporary therapy of the menopausal syndrome.” Journal of the American Medical Association 171.12 (1959): 1627–37.

Halmesmäki, K., Hurskainen, R., Tiitinen, A., et al. “A randomized controlled trial hysterectomy of levenorgestrelreleasing intrauterine system in the treatment of menorrhagia – effect of FSH levels and menopausal symptoms.” Human Reproduction 19.2 (2004): 378–82.

Geller, S.E., Shulman, L.P., van Breemen, R.B., et al. “Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial.” Menopause 16.6 (2009): 1156–66.

Schneider, H.P.G., Heinemann, L.A.J., Rosemeier, H.P., et al. “The menopause rating scale (MRS): comparison with Kupperman index and quality-of-life scale SF-36.” Climacteric 3.1 (2000): 50–8.

Todorova, M., Kamenov, Z., Baleva, M., Christov, V., Nicolov, K. “Anticardiolipin antibodies during hormone replacement therapy in healthy postmenopausal women.” Maturitas 48.4 (2004): 393–7.

Zaborowska, E., Brynhildsen, J., Damberg, S., et al. “Effects of acupuncture, applied relaxation, estrogens and placebo on hot flushes in postmenopausal women: an analysis of two prospective, parallel, randomized studies.” Climacteric 10.1 (2007): 38–45.

Rauš, K., Brucker, C., Gorkow, C., Wuttke, W. “First- time proof of endometrial safety of the special black cohosh extract (Actaea or Cimicifuga racemosa extract) CR BNO 1055.” Menopause 13.4 (2006): 678–91.

Pockaj, B.A., Gallagher, J.G., Loprinzi, C.L., et al. “Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG trial N01CC.” Journal of Clinical Oncology 24.18 (2006): 2836–41.


GOST Style Citations


1. Dennerstein, L., Guthrie, J., Birkhäuser, M., et al. “Symptoms of the menopause.” In International Position Paper on Women’s Health and Menopause: A Comprehensive Approach, ed. by N.K. Wenger, C.J.M. Lenfant, R. Paoletti, and V.W. Pinn. NIH Publication 02–3284. National Heart, Lung, and Blood Institute. Office of Research in Woman’s Health (2002).

2. Green, R., Santoro, N. “Menopausal symptoms and ethnicity: the Study of Women’s Health Across the Nation.” Women’s Health 5.2 (2009): 127–33.

3. Thurston, R.C., Joffe, H. “Vasomotor symptoms and menopause: findings from the study of women’s health across the nation.” Obstet Gynecol Clinics of North America 38.3 (2011): 489–501.

4. Kronenberg, F. “Hot flashes: epidemiology and physiology.” Annals of the New York Academy of Sciences 592 (1990): 52–86.

5. Nakano, K., Pinnow, E., Flaws, J.A., et al. “Reproductive history and hot flashes in perimenopausal women.” Journal of Women’s Health 21.4 (2012): 433–9.

6. Hunter, M.S., Gentry-Maharaj, A., Ryan, A., et al. “Prevalence, frequency and problem rating of hot flushes persist in older postmenopausal women: Impact of age, body mass index, hysterectomy, hormone therapy use, lifestyle and mood in a cross-sectional cohort study of 10 418 British women aged 54–65.” An International Journal of Obstetrics and Gynaecology 119.1 (2012): 40–50.

7. Joffe, H., Soares, C.N., Cohen, L.S. “Assessment and treatment of hot flushes and menopausal mood disturbance.” Psychiatric Clinics of North America 26.3 (2003): 563–80.

8. Ohayon, M.M. “Severe hot flashes are associated with chronic insomnia.” Archives of Internal Medicine 166.12 (2006): 1262–8.

9. MacLennan, A., Lester, S., Moore, V. “Oral oestrogen replacement therapy versus placebo for hot flushes.” Cochrane Database Sys Rev 1 (2001): CD002978.

10. Maclennan, A.H., Broadbent, J.L., Lester, S., Moore, V. “Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes.” Cochrane Database Sys Rev 4 (2004): CD002978.

11. Sturdee, D.W. “The menopausal hot flush – anything new?” Maturitas 60.1 (2008): 42–9.

12. Collaborative Group on Hormonal Factors in Breast Cancer. “Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52.705 women with breast cancer and 108.411 women without breast cancer.” Lancet 350.9084 (1997): 1047–59.

13. Beral, V. “Breast cancer and hormone-replacement therapy in the Million Women Study.” Lancet 362.9382 (2003): 419–27.

14. Chlebowski, R.T., Hendrix, S.L., Langer, R.D., et al. “Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the women’s health initiative randomized trial.” Journal of the American Medical Association 289.24 (2003): 3243–53.

15. Stefanick, M.L., Anderson, G.L., Margolis, K.L., et al. “Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy.” Journal of the American Medical Association 295.14 (2006): 1647–57.

16. ESCOP, Cimicifugae Rhizoma. Black Cohosh, ESCOP Monographs, Scientific Foundation for Herbal Medicinal Products. Georg Thieme-Verlag. Stuttgart. Germany. 2nd edition (2003).

17. Committee on Herbal Medicinal Products (HMPC). “Community herbal monograph on Cimicifuga racemosa (L.) Nutt., rhizoma., European Medicines Agency.” Vol. EMA/ HMPC/600717/2007 (2010).

18. Reed, S.D., Newton, K.M., LaCroix, A.Z., et al. “Vaginal, endometrial, and reproductive hormone findings: Randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) Study.” Menopause 15.1 (2008): 51–8.

19. Wuttke, W., Gorkow, C., Seidlova-Wuttke, D. “Effects of black cohosh (Cimicifuga racemosa) on bone turnover, vaginal mucosa, and various blood parameters in postmenopausal women: a double-blind, placebo-controlled, and conjugated estrogens-controlled study.” Menopause 13.2 (2006): 185–96.

20. Wuttke, W., Seidlova-Wuttke, D., Gorkow, C. “The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers.” Maturitas 44 (2003): 67–77.

21. Oktem, M., Eroglu, D., Karahan, H.B., et al. “Black cohosh and fluoxetine in the treatment of postmenopausal symptoms: a prospective, randomized trial.” Advances in Therapy 24.2 (2007): 448–61.

22. Ruhlen, R.L., Sun, G.Y., Sauter, E.R. “Black cohosh: insights into its mechanism(s) of action.” Integrative Medicine Insights 3 (2008): 21–32.

23. Osmers, R., Friede, M., Liske, E., et al. “Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms.” Obstet Gynecol 105.5.1 (2005): 1074–83.

24. Stoll, W. “Phytotherapeuticon influences atrophic vaginal epithelium.” Therapeutikon 1.23 (1987): 23–31.

25. Liske, E., Hänggi, W., Henneicke-von Zepelin, H.-H., et al. “Physiological investigation of a unique extract of black cohosh (Cimicifugae racemosae rhizoma): A 6-month clinical study demonstrates no systemic estrogenic effect.” Journal of Women’s Health and Gender-Based Medicine 11.2 (2002): 163–74.

26. Bai, W., Henneicke-von Zepelin, H.-H., Wang, S., et al. “Efficacy and tolerability of a medicinal product containing an isopropanolic black cohosh extract in Chinese women with menopausal symptoms: a randomized, double blind, parallelcontrolled study versus tibolone.” Maturitas 58.1 (2007): 31–41.

27. Aidelsburger, P., Schauer, S., Grabein, K., et al. “Alternative methods for the treatment of post-menopausal troubles.” GMS Health Technology Assessment 8 (2012): Doc03.

28. Borrelli, F., Ernst, E. “Alternative and complementary therapies for the menopause.” Maturitas 66.4 (2010): 333–43.

29. Wong, V.C.K., Lim, C.E.D., Luo, X., Wong, W.S.F. “Current alternative and complementary therapies used in menopause.” Gynecological Endocrinology 25.3 (2009): 166–74.

30. Palacio, C., Masri, G., Mooradian, A.D. “Black cohosh for the management of menopausal symptoms: a systematic review of clinical trials.” Drugs and Aging 26.1 (2009): 23–36.

31. Shams, T., Setia, M.S., Hemmings, R., et al. “Efficacy of black cohosh-containing preparations on menopausal symptoms: a meta-analysis.” Alternative Therapies in Health and Medicine 16.1 (2010): 36–44.

32. Kupperman, S., Wetchler, B.B., Blatt, M.H. “Contemporary therapy of the menopausal syndrome.” Journal of the American Medical Association 171.12 (1959): 1627–37.

33. Halmesmäki, K., Hurskainen, R., Tiitinen, A., et al. “A randomized controlled trial hysterectomy of levenorgestrelreleasing intrauterine system in the treatment of menorrhagia – effect of FSH levels and menopausal symptoms.” Human Reproduction 19.2 (2004): 378–82.

34. Geller, S.E., Shulman, L.P., van Breemen, R.B., et al. “Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial.” Menopause 16.6 (2009): 1156–66.

35. Schneider, H.P.G., Heinemann, L.A.J., Rosemeier, H.P., et al. “The menopause rating scale (MRS): comparison with Kupperman index and quality-of-life scale SF-36.” Climacteric 3.1 (2000): 50–8.

36. Todorova, M., Kamenov, Z., Baleva, M., Christov, V., Nicolov, K. “Anticardiolipin antibodies during hormone replacement therapy in healthy postmenopausal women.” Maturitas 48.4 (2004): 393–7.

37. Zaborowska, E., Brynhildsen, J., Damberg, S., et al. “Effects of acupuncture, applied relaxation, estrogens and placebo on hot flushes in postmenopausal women: an analysis of two prospective, parallel, randomized studies.” Climacteric 10.1 (2007): 38–45.

38. Rauš, K., Brucker, C., Gorkow, C., Wuttke, W. “First- time proof of endometrial safety of the special black cohosh extract (Actaea or Cimicifuga racemosa extract) CR BNO 1055.” Menopause 13.4 (2006): 678–91.

39. Pockaj, B.A., Gallagher, J.G., Loprinzi, C.L., et al. “Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG trial N01CC.” Journal of Clinical Oncology 24.18 (2006): 2836–41.





DOI: http://dx.doi.org/10.18370/2309-4117.2016.29.80-89

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